Osteoporosis is a condition of excessive skeletal fragility in elderly women. Though it can be prevented by slowing adulthood bone loss, today's most challenging problems are to permanently improve bone strength by adding and maintaining bone mass in fracturing subjects, and understand the building of peak bone mass and its implications for the future. We propose four small animal experiments, and plan histomorphometric, densitometric, and ultrasound techniques for evaluating bone mass and structure, bone formation, and bone resorption activity. Usually, we will allow adult ovariectomized rats to become osteopenic for ten weeks and then intervene. First, we will treat with human parathyroid hormone (hPTH). We hypothesize that PTH, possibly a prototype skeletal anabolic agent, has a dose-effect relationship for raising bone mass, but that bone mass cannot rise indefinitely. We will calcium supplement some PTH-treated rats. We hypothesize that adding calcium will improve PTH's anabolic actions because of the large demands for calcium by bone forming cells. Next, we will raise bone mass with PTH, but switch to a maintenance program of anti- resorptive agents (estrogen or bisphosphonates). We hypothesize that they will preserve the increased bone mass. In the same osteopenic model, we will try gonadal steroid combinations. We hypothesize that: progesterone in anabolic, re-establishing normal hormone levels of the estrus cycle rebuilds lost bone mass, and low dose estrogen+ progesterone therapy (see Project 2 of this SCOR), stimulates bone formation. Finally, in rats, we will induce reversible medical ovariectomy during early or late growth periods. We hypothesize that peak bone mass and structure are negatively affected by estrogen deficiency when final cancellous structures are forming, but not at other times. We expect to provide improved knowledge of in vivo behavior of PTH, and perhaps build a framework for understanding future skeletal anabolic agents. Showing that existing anti-resorptive agents can be substituted for scarce, expensive anabolic agents after bone mass has been rebuilt, to maintain the new bone, would be valuable. We expect to extend knowledge about the positive skeletal effects of gonadal steroid replacement in the osteopenic skeleton. Finally, understanding the lasting skeletal effects of transient estrogen-deficiencies during different phases of growth could help the long term effort to improve peak bone mass.